Axitinib blocks Wnt/β-catenin signaling and directs asymmetric cell division in cancer

Yi Qu, Naouel Gharbi, Xing Yuan, Jan Roger Olsen, Pernille Blicher, Bjørn Dalhus, Karl A. Brokstad, Biaoyang Lin, Anne Margrete Øyan, Weidong Zhang, Karl-Henning Kalland, and Xisong Ke

Proceedings of the National Academy of Sciences of the United States of America
2016 vol: 113 issue: 33 pp: 9339-9344 doi: 10.1073/pnas.1604520113

Abstract
Oncogenic mutations of the Wnt (wingless)/β-catenin pathway are frequently observed in major cancer types. Thus far, however, no therapeutic agent targeting Wnt/β-catenin signaling is available for clinical use. Here we demonstrate that axitinib, a clinically approved drug, strikingly blocks Wnt/β-catenin signaling in cancer cells, zebrafish, and Apc(min/+) mice. Notably, axitinib dramatically induces Wnt asymmetry and nonrandom DNA segregation in cancer cells by promoting nuclear β-catenin degradation independent of the GSK3β (glycogen synthase kinase3β)/APC (adenomatous polyposis coli) complex. Using a DARTS (drug affinity-responsive target stability) assay coupled to 2D-DIGE (2D difference in gel electrophoresis) and mass spectrometry, we have identified the E3 ubiquitin ligase SHPRH (SNF2, histone-linker, PHD and RING finger domain-containing helicase) as the direct target of axitinib in blocking Wnt/β-catenin signaling. Treatment with axitinib stabilizes SHPRH and thereby increases the ubiquitination and degradation of β-catenin. Our findings suggest a previously unreported mechanism of nuclear β-catenin regulation and indicate that axitinib, a clinically approved drug, would provide therapeutic benefits for cancer patients with aberrant nuclear β-catenin activation.

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Topics: Axitinib, β-catenin, Asymmetric cell division, SHPRH, Monolith – MicroScale Thermophoresis, MST, Proteins, Publications